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href=\u0022https:\/\/www.bmj.com\/sites\/default\/files\/advagg_css\/css__GkPSKUkdJ2bzIT9BLdob0bbh88SFHg9JxcNgbdHlbDc__qYTxeL-KKGqFiuvt1Pd7tJWAZkcDxAZN7jCKDHxZcE0__b2e6faiQ_UWIrIhhy-1_GBi9M1f1xMsmWzx8NA2PKwk.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-jnl-bmj-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n \n \n \n \u003Cdiv class=\u0022pane-content\u0022\u003E\n \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 data-highwire-cite-ref-tooltip-instance=\u0022highwire_reflinks_tooltip\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view\u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022contributors\u0022\u003E\u003Col class=\u0022contributor-list\u0022 id=\u0022contrib-group-1\u0022\u003E\u003Cli class=\u0022contributor\u0022 id=\u0022contrib-1\u0022\u003E\u003Cspan class=\u0022name\u0022\u003EClare Relton\u003C\/span\u003E\u003Cspan class=\u0022contrib-role\u0022\u003E, research fellow\u003C\/span\u003E\u003Ca id=\u0022xref-aff-1-1\u0022 class=\u0022xref-aff\u0022 href=\u0022#aff-1\u0022\u003E1\u003C\/a\u003E\u003Ca id=\u0022xref-aff-3-1\u0022 class=\u0022xref-aff\u0022 href=\u0022#aff-3\u0022\u003E3\u003C\/a\u003E, \u003C\/li\u003E\u003Cli class=\u0022contributor\u0022 id=\u0022contrib-2\u0022\u003E\u003Cspan class=\u0022name\u0022\u003EDavid Torgerson\u003C\/span\u003E\u003Cspan class=\u0022contrib-role\u0022\u003E, director of clinical trials unit\u003C\/span\u003E\u003Ca id=\u0022xref-aff-2-1\u0022 class=\u0022xref-aff\u0022 href=\u0022#aff-2\u0022\u003E2\u003C\/a\u003E, \u003C\/li\u003E\u003Cli class=\u0022contributor\u0022 id=\u0022contrib-3\u0022\u003E\u003Cspan class=\u0022name\u0022\u003EAlicia O\u2019Cathain\u003C\/span\u003E\u003Cspan class=\u0022contrib-role\u0022\u003E, professor of health services research\u003C\/span\u003E\u003Ca id=\u0022xref-aff-1-2\u0022 class=\u0022xref-aff\u0022 href=\u0022#aff-1\u0022\u003E1\u003C\/a\u003E, \u003C\/li\u003E\u003Cli class=\u0022last\u0022 id=\u0022contrib-4\u0022\u003E\u003Cspan class=\u0022name\u0022\u003EJon Nicholl\u003C\/span\u003E\u003Cspan class=\u0022contrib-role\u0022\u003E, director of the Medical Care Research Unit\u003C\/span\u003E\u003Ca id=\u0022xref-aff-1-3\u0022 class=\u0022xref-aff\u0022 href=\u0022#aff-1\u0022\u003E1\u003C\/a\u003E\u003C\/li\u003E\u003C\/ol\u003E\u003Col class=\u0022affiliation-list\u0022\u003E\u003Cli class=\u0022aff\u0022\u003E\u003Ca id=\u0022aff-1\u0022 name=\u0022aff-1\u0022\u003E\u003C\/a\u003E\u003Caddress\u003E\u003Csup\u003E1\u003C\/sup\u003ESchool for Health and Related Research, University of Sheffield, Sheffield\u003C\/address\u003E\u003C\/li\u003E\u003Cli class=\u0022aff\u0022\u003E\u003Ca id=\u0022aff-2\u0022 name=\u0022aff-2\u0022\u003E\u003C\/a\u003E\u003Caddress\u003E\u003Csup\u003E2\u003C\/sup\u003EDepartment of Health Sciences, University of York, Heslington, York\u003C\/address\u003E\u003C\/li\u003E\u003Cli class=\u0022aff\u0022\u003E\u003Ca id=\u0022aff-3\u0022 name=\u0022aff-3\u0022\u003E\u003C\/a\u003E\u003Caddress\u003E\u003Csup\u003E3\u003C\/sup\u003ESchool of Healthcare, University of Leeds, Leeds\u003C\/address\u003E\u003C\/li\u003E\u003C\/ol\u003E\u003Col class=\u0022corresp-list\u0022\u003E\u003Cli class=\u0022corresp\u0022 id=\u0022corresp-1\u0022\u003ECorrespondence to: C Relton \u003Cspan class=\u0022em-link\u0022\u003E\u003Cspan class=\u0022em-addr\u0022\u003Ec.relton{at}sheffield.ac.uk\u003C\/span\u003E\u003C\/span\u003E\u003C\/li\u003E\u003C\/ol\u003E\u003Cul class=\u0022history-list\u0022\u003E\u003Cli xmlns:hwp=\u0022http:\/\/schema.highwire.org\/Journal\u0022 class=\u0022accepted\u0022 hwp:start=\u00222009-11-16\u0022\u003E\u003Cspan class=\u0022accepted-label\u0022\u003EAccepted \u003C\/span\u003E16 November 2009\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022teaser\u0022\u003E\u003Cp id=\u0022p-1\u0022\u003EPragmatic trials are important for informing routine clinical practice, but current designs have shortcomings. \u003Cstrong\u003EClare Relton and colleagues\u003C\/strong\u003E outline the new \u201ccohort multiple randomised controlled trial\u201d design, which could help address the problems associated with existing approaches\u003C\/p\u003E\u003C\/div\u003E\u003Cdiv class=\u0022source-body\u0022\u003E\u003Cdiv class=\u0022section intro\u0022 id=\u0022intro\u0022\u003E\u003Ch2\u003EIntroduction\u003C\/h2\u003E\u003Cp id=\u0022p-2\u0022\u003ERandomised controlled trials are generally held to be the \u201cgold standard\u201d for establishing how well an intervention works. Trials that aim to determine the efficacy of a treatment by using a double blind, placebo controlled design (that is, explanatory trials) are, however, sometimes criticised. For example, although the design of explanatory trials results in strong internal validity\u2014we can depend upon the results of a given trial\u2014such trials may have limited external validity: we can\u2019t be confident that we can apply the results to routine clinical practice. Pragmatic trials,\u003Ca id=\u0022xref-ref-1-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-1\u0022\u003E1\u003C\/a\u003E \u003Ca id=\u0022xref-ref-2-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-2\u0022\u003E2\u003C\/a\u003E which aim to inform healthcare decision making in practice, have been offered as a solution in that they retain the rigour of randomisation (thus eliminate selection bias) but retain the characteristics of normal clinical practice. \u003C\/p\u003E\u003Cp id=\u0022p-3\u0022\u003EThe implementation and interpretation of both pragmatic and explanatory randomised controlled trials are associated with significant problems. This article describes a trial design that helps address these problems\u2014the \u201ccohort multiple randomised controlled trial\u201d approach.\u003C\/p\u003E\u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-2\u0022\u003E\u003Ch2\u003EProblems with randomised controlled trials\u003C\/h2\u003E\u003Cp id=\u0022p-4\u0022\u003EExisting clinical trial designs can have shortcomings in four areas: recruitment; ethics; patient preferences; and treatment comparisons.\u003C\/p\u003E\u003Cdiv id=\u0022sec-3\u0022 class=\u0022subsection\u0022\u003E\u003Ch3\u003ERecruitment\u003C\/h3\u003E\u003Cp id=\u0022p-5\u0022\u003EThe majority of randomised controlled trials have difficulty recruiting sufficient numbers of patients. For example, one investigation found that less than a third of 114 multicentre, publicly funded UK trials recruited their original target number of patients within the time originally specified.\u003Ca id=\u0022xref-ref-3-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-3\u0022\u003E3\u003C\/a\u003E Failure to recruit to target may have implications for the power and generalisability of trial results. \u003C\/p\u003E\u003Cp id=\u0022p-6\u0022\u003EMoreover, many clinical trials exclude hard to reach groups and ethnic minorities,\u003Ca id=\u0022xref-ref-4-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-4\u0022\u003E4\u003C\/a\u003E resulting in disparities between the \u201cwith need\u201d (reference) population and the trial population.\u003Ca id=\u0022xref-ref-5-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-5\u0022\u003E5\u003C\/a\u003E \u003Ca id=\u0022xref-ref-6-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-6\u0022\u003E6\u003C\/a\u003E Measures of real world effectiveness are vital for analyses of benefit, harm, and cost effectiveness. If the reference population is not adequately represented in a trial and effectiveness is variable, then such analyses cannot accurately inform real world decisions.\u003C\/p\u003E\u003C\/div\u003E\u003Cdiv id=\u0022sec-4\u0022 class=\u0022subsection\u0022\u003E\u003Ch3\u003EEthics\u003C\/h3\u003E\u003Cp id=\u0022p-7\u0022\u003EThe most common reason given by patients (and clinicians) for not participating in clinical trials is \u201cconcerns with information and consent.\u201d\u003Ca id=\u0022xref-ref-7-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-7\u0022\u003E7\u003C\/a\u003E In routine real world health care, patients are rarely told of treatments that their clinicians cannot with certainty provide,\u003Ca id=\u0022xref-ref-8-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-8\u0022\u003E8\u003C\/a\u003E nor are patients told their treatment will be decided by chance. On the other hand, in clinical trials providing this type of \u201cfull\u201d information before randomisation is regarded as an ethical requirement.\u003C\/p\u003E\u003C\/div\u003E\u003Cdiv id=\u0022sec-5\u0022 class=\u0022subsection\u0022\u003E\u003Ch3\u003EPatient preferences\u003C\/h3\u003E\u003Cp id=\u0022p-8\u0022\u003EStandard \u201copen\u201d (unblinded) pragmatic trials often compare an intervention with treatment as usual. Where the \u201cstandard care\u201d on offer is available outside the trial, however, the only incentive for the patient to participate (apart from altruism) is to receive the new intervention. If a patient is allocated to treatment as usual, he or she may withdraw from the trial (attrition bias) or exhibit disappointment bias when reporting outcomes.\u003Ca id=\u0022xref-ref-9-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-9\u0022\u003E9\u003C\/a\u003E\u003C\/p\u003E\u003C\/div\u003E\u003Cdiv id=\u0022sec-6\u0022 class=\u0022subsection\u0022\u003E\u003Ch3\u003ETreatment comparisons\u003C\/h3\u003E\u003Cp id=\u0022p-9\u0022\u003EA common research scenario is addressing a clinical problem with many potential treatments. Yet often each potential treatment is trialled, one at a time, in different populations by different research teams. This approach yields many trials of different interventions, with heterogeneous trial populations and often short term and heterogeneous outcomes\u2014a situation that is both financially and scientifically inefficient on three counts. \u003C\/p\u003E\u003Cp id=\u0022p-10\u0022\u003EFirstly, lack of collection of long term outcomes hinders the measurement of infrequent adverse events and outcomes that occur far in the future. Secondly, systematic reviews of studies on a particular topic often conclude that \u201cthere was heterogeneity in populations and outcomes\u201d; thus greater homogeneity in trial outcomes and populations is required to be able to synthesise the results of trials effectively. Thirdly, heterogeneity of trial populations and outcomes presents difficulties when making indirect comparisons between interventions; for example, the effectiveness of treatments A versus C, where only trials of treatments A versus B and B versus C exist. Indirect comparisons\u2014where two interventions are compared through their relative effect versus a common comparator\u2014can succeed, but sometimes result in significant discrepancies compared with the results of head to head randomised trials.\u003Ca id=\u0022xref-ref-10-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-10\u0022\u003E10\u003C\/a\u003E Many competing interventions have thus not been compared, or have been compared inaccurately, which is a waste of valuable information and money.\u003C\/p\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-7\u0022\u003E\u003Ch2\u003EPrevious solutions\u003C\/h2\u003E\u003Cp id=\u0022p-11\u0022\u003EThree alternative trial designs have attempted to address the recruitment and patient preferences issues inherent in existing clinical trial designs: the patient preference,\u003Ca id=\u0022xref-ref-11-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-11\u0022\u003E11\u003C\/a\u003E comprehensive cohort,\u003Ca id=\u0022xref-ref-12-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-12\u0022\u003E12\u003C\/a\u003E \u003Ca id=\u0022xref-ref-13-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-13\u0022\u003E13\u003C\/a\u003E and randomised consent (Zelen) designs.\u003Ca id=\u0022xref-ref-14-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-14\u0022\u003E14\u003C\/a\u003E \u003C\/p\u003E\u003Cp id=\u0022p-12\u0022\u003EBoth the patient preference design and the comprehensive cohort design make some allowance for patient preferences regarding random allocation or type of treatment by collecting data from both randomised and non-randomised patients, thus increasing the overall number of patients recruited but not the numbers randomised. Both these designs have the limitation that if large numbers of patients express a preference, there might be insufficient \u201cindifferent\u201d patients available to be randomised. Designs where patients are asked their preferences and randomised irrespective of these will not necessarily solve problems of attrition or failure to recruit participants with a very strong preference.\u003Ca id=\u0022xref-ref-15-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-15\u0022\u003E15\u003C\/a\u003E \u003C\/p\u003E\u003Cp id=\u0022p-13\u0022\u003EIn randomised consent (Zelen) designs, consent is sought after randomisation. However, these designs are subject to ethical criticisms, such as the lack of information regarding all trial treatment options to all patients, and scientific criticism, because of the dilution of effect owing to \u201ccross-over\u201d of patients to the non-randomised treatment. Despite these criticisms, reviews report the existence of more than 60 randomised consent designs with ethics committee approval.\u003Ca id=\u0022xref-ref-16-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-16\u0022\u003E16\u003C\/a\u003E \u003Ca id=\u0022xref-ref-17-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-17\u0022\u003E17\u003C\/a\u003E \u003Ca id=\u0022xref-ref-18-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-18\u0022\u003E18\u003C\/a\u003E\u003C\/p\u003E\u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-8\u0022\u003E\u003Ch2\u003EThe \u201ccohort multiple randomised controlled trial\u201d design\u003C\/h2\u003E\u003Cp id=\u0022p-14\u0022\u003ETo address some of the shortcomings of existing trial designs we propose a new approach primarily for pragmatic randomised controlled trials\u2014the \u201ccohort multiple randomised controlled trial\u201d (cmRCT) design (figure\u003Ca id=\u0022xref-fig-1-1\u0022 class=\u0022xref-down-link\u0022 href=\u0022#F1\u0022\u003E\u003Cspan\u003E\u21d3\u003C\/span\u003E\u003C\/a\u003E). \u003C\/p\u003E\u003Cdiv id=\u0022F1\u0022 class=\u0022fig pos-float odd\u0022\u003E\u003Cdiv class=\u0022fig-inline\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022https:\/\/www.bmj.com\/content\/bmj\/340\/bmj.c1066\/F1.large.jpg?width=800\u0026amp;height=600\u0022 title=\u0022The \u0026#x201C;cohort multiple randomised controlled trial\u0026#x201D; design. Firstly, a large observational cohort of patients with the condition of interest is recruited (N) and their outcomes regularly measured. Then for each randomised controlled trial, information from the cohort is used to identify all eligible patients (NA). Some eligible patients (nA) are randomly selected and offered the trial intervention. The outcomes of these randomly selected patients (nA) are then compared with the outcomes of eligible patients not randomly selected; that is, those receiving usual care (NA \u0026#x2212; nA). This process can be repeated for further randomised controlled trials (for example, NB)\u0022 class=\u0022colorbox fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images\u0022 data-figure-caption=\u0022\u0026lt;div class=\u0026quot;highwire-markup\u0026quot;\u0026gt;\u0026lt;div class=\u0026quot;fig-caption\u0026quot; xmlns:xhtml=\u0026quot;http:\/\/www.w3.org\/1999\/xhtml\u0026quot;\u0026gt;\u0026lt;p id=\u0026quot;p-15\u0026quot; class=\u0026quot;first-child\u0026quot;\u0026gt;The \u0026#x201C;cohort multiple randomised controlled trial\u0026#x201D; design. Firstly, a large observational cohort of patients with the condition of interest is recruited (N) and their outcomes regularly measured. Then for each randomised controlled trial, information from the cohort is used to identify all eligible patients (NA). Some eligible patients (nA) are randomly selected and offered the trial intervention. The outcomes of these randomly selected patients (nA) are then compared with the outcomes of eligible patients not randomly selected; that is, those receiving usual care (NA \u0026#x2212; nA). This process can be repeated for further randomised controlled trials (for example, NB)\u0026lt;\/p\u0026gt;\u0026lt;div class=\u0026quot;sb-div caption-clear\u0026quot;\u0026gt;\u0026lt;\/div\u0026gt;\u0026lt;\/div\u0026gt;\u0026lt;\/div\u0026gt;\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 src=\u0022https:\/\/www.bmj.com\/content\/bmj\/340\/bmj.c1066\/F1.medium.gif\u0022 alt=\u0022Figure1\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cdiv xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 class=\u0022fig-caption\u0022\u003E\u003Cp id=\u0022p-15\u0022 class=\u0022first-child\u0022\u003EThe \u201ccohort multiple randomised controlled trial\u201d design. Firstly, a large observational cohort of patients with the condition of interest is recruited (N) and their outcomes regularly measured. Then for each randomised controlled trial, information from the cohort is used to identify all eligible patients (NA). Some eligible patients (nA) are randomly selected and offered the trial intervention. The outcomes of these randomly selected patients (nA) are then compared with the outcomes of eligible patients not randomly selected; that is, those receiving usual care (NA \u2212 nA). This process can be repeated for further randomised controlled trials (for example, NB)\u003C\/p\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links list-inline\u0022\u003E\u003Cli class=\u0022download-fig first\u0022\u003E\u003Ca href=\u0022https:\/\/www.bmj.com\/content\/bmj\/340\/bmj.c1066\/F1.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure1\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\n\u003Cli class=\u0022new-tab\u0022\u003E\u003Ca href=\u0022https:\/\/www.bmj.com\/content\/bmj\/340\/bmj.c1066\/F1.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\n\u003Cli class=\u0022download-ppt last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/590407\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\n\u003C\/ul\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-16\u0022\u003EThe key features of this design are:\u003C\/p\u003E\u003Cul class=\u0022list-simple\u0022 id=\u0022list-1\u0022\u003E\u003Cli id=\u0022list-item-1\u0022\u003E\u003Cp id=\u0022p-17\u0022\u003E(I) Recruitment of a large observational cohort of patients with the condition of interest\u003C\/p\u003E\u003C\/li\u003E\u003Cli id=\u0022list-item-2\u0022\u003E\u003Cp id=\u0022p-18\u0022\u003E(II) Regular measurement of outcomes for the whole cohort\u003C\/p\u003E\u003C\/li\u003E\u003Cli id=\u0022list-item-3\u0022\u003E\u003Cp id=\u0022p-19\u0022\u003E(III) Capacity for multiple randomised controlled trials over time\u003C\/p\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003Cp id=\u0022p-20\u0022\u003EFor each randomised controlled trial:\u003C\/p\u003E\u003Cul class=\u0022list-simple\u0022 id=\u0022list-2\u0022\u003E\u003Cli id=\u0022list-item-4\u0022\u003E\u003Cp id=\u0022p-21\u0022\u003E(IV) Identification of all eligible patients in the whole cohort (NA)\u003C\/p\u003E\u003C\/li\u003E\u003Cli id=\u0022list-item-5\u0022\u003E\u003Cp id=\u0022p-22\u0022\u003E(V) Random selection of some patients (nA) from all eligible patients in the cohort, who are then offered the trial intervention\u003C\/p\u003E\u003C\/li\u003E\u003Cli id=\u0022list-item-6\u0022\u003E\u003Cp id=\u0022p-23\u0022\u003E(VI) Comparison of the outcomes in randomly selected patients (nA) with the outcomes in eligible patients not randomly selected; that is, those receiving usual care (NA \u2212 nA)\u003C\/p\u003E\u003C\/li\u003E\u003Cli id=\u0022list-item-7\u0022\u003E\u003Cp id=\u0022p-24\u0022\u003E(VII) \u201cPatient centred\u201d informed consent; that is, the process of obtaining patient information and consent aims to replicate that in real world routine health care.\u003C\/p\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003Cp id=\u0022p-25\u0022\u003EThe recruitment and regular follow-up of a large cohort of patients (features I and II) are characteristic of longitudinal observational studies. In the cmRCT design, however, all patients in the cohort consent at the outset to provide data to be used to look at the benefit of treatments for the condition of interest. Feature III, the capacity for multiple randomised controlled trials over time using patients from the same cohort, is unique to the cmRCT design. Random selection of some eligible cohort patients (feature V), the comparison of their outcomes with the outcomes in eligible patients not randomly selected (feature VI), and the similarity of the patient centred informed consent approach to real life situations (feature VII) offer solutions to the ethical criticisms of randomised consent (Zelen) designs.\u003C\/p\u003E\u003Cdiv id=\u0022sec-9\u0022 class=\u0022subsection\u0022\u003E\u003Ch3\u003ERandomisation: random selection of some\u003C\/h3\u003E\u003Cp id=\u0022p-26\u0022\u003EFeature V and VI offer an alternative process for randomisation in clinical trials. The purpose of randomisation in experimental research is to generate two or more groups whose selection and treatment have not been influenced by anyone or anything other than chance and where all known or unknown prognostic factors are distributed evenly at baseline. Generating two groups whose membership is a result of chance can be achieved by either random allocation of all participants or random selection of some, because each approach produces the same effect. The random selection of nA patients from all patients (NA) in our example has the same effect as the random allocation of NA into two groups, nA and nB, because it is solely owing to chance whether any one patient is selected into nA. For the purposes of a randomised controlled trial, random selection from NA into nA provides two groups where all known or unknown prognostic factors are distributed at baseline purely by chance: nA and (NA \u2212 nA).\u003C\/p\u003E\u003Cp id=\u0022p-27\u0022\u003ERandomisation is generally conceived as \u201crandom allocation of all\u201d and as something that is \u201cdone\u201d to all patients, and thus requires their prior consent. With randomisation conceived of as \u201crandom selection of some,\u201d however, then nothing is \u201cdone\u201d to all patients and prior consent of all patients is not required.\u003C\/p\u003E\u003C\/div\u003E\u003Cdiv id=\u0022sec-10\u0022 class=\u0022subsection\u0022\u003E\u003Ch3\u003EInformation and consent: \u201cpatient centred\u201d\u003C\/h3\u003E\u003Cp id=\u0022p-28\u0022\u003EThe final feature of the cmRCT design (feature VII) is the adoption of a \u201cpatient centred\u201d approach to informed consent, in which the process of obtaining patient information and consent aims to replicate that in real world routine health care rather than conform to the needs of trial design. All cohort patients consent to provide observational data at the outset; however, consent to \u201ctry\u201d a particular intervention is sought only from those offered that intervention, thus replicating the patient centred information and consent procedures that exist in routine health care, where clinicians provide patients with the information they need, at the time they need it. \u003C\/p\u003E\u003Cp id=\u0022p-29\u0022\u003EThe rationale for this approach is twofold. Firstly, the primary motive for patients to enter clinical trials is not altruism, but their own direct benefit as patients.\u003Ca id=\u0022xref-ref-19-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-19\u0022\u003E19\u003C\/a\u003E Clinical trial informed consent procedures should, therefore, put the needs of the patient at the centre; that is, patients should not be told about treatments that they might not then receive, nor should they be told that their treatment will be allocated by chance. Secondly, the greater the similarity between patients\u2019 experiences in trials and their experiences in routine health care, then the greater the generalisability of the trial results to patients in routine health care.\u003C\/p\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-11\u0022\u003E\u003Ch2\u003EBenefits of the approach\u003C\/h2\u003E\u003Cp id=\u0022p-30\u0022\u003EThe cmRCT design will, we believe, help to address some of the shortcomings that prevent many pragmatic randomised controlled trials fulfilling their potential of giving robust evidence that clinicians can apply to their usual clinical populations.\u003C\/p\u003E\u003Cp id=\u0022p-31\u0022\u003ECompared with randomised controlled trials, longitudinal observational studies can recruit a greater quantity and more representative sample of patients. Moreover, compared with doing individual pragmatic trials, using an observational cohort has important additional benefits:\u003C\/p\u003E\u003Cul class=\u0022list-simple\u0022 id=\u0022list-3\u0022\u003E\u003Cli id=\u0022list-item-8\u0022\u003E\u003Cp id=\u0022p-32\u0022\u003EA A facility for multiple randomised controlled trials\u003C\/p\u003E\u003C\/li\u003E\u003Cli id=\u0022list-item-9\u0022\u003E\u003Cp id=\u0022p-33\u0022\u003EB Long term outcomes as standard\u003C\/p\u003E\u003C\/li\u003E\u003Cli id=\u0022list-item-10\u0022\u003E\u003Cp id=\u0022p-34\u0022\u003EC Ongoing information as to the natural history of the condition and to treatment as usual\u003C\/p\u003E\u003C\/li\u003E\u003Cli id=\u0022list-item-11\u0022\u003E\u003Cp id=\u0022p-35\u0022\u003ED Increased comparability between each trial conducted within the cohort\u003C\/p\u003E\u003C\/li\u003E\u003Cli id=\u0022list-item-12\u0022\u003E\u003Cp id=\u0022p-36\u0022\u003EE Increased efficiency, particularly for expensive or high risk interventions\u003C\/p\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003Cp id=\u0022p-37\u0022\u003EThe cmRCT approach enables more reliable direct and indirect comparisons than is possible with trials conducted using current randomised controlled trial designs because all treatments have the same \u201ctreatment as usual\u201d comparator and use the same core outcomes. \u003C\/p\u003E\u003Cp id=\u0022p-38\u0022\u003EFurthermore, researchers using standard randomised controlled trial designs often struggle to recruit and consequently have to randomly allocate all patients to either group in equal proportions to maximise statistical power within their total sample. The large numbers of patients recruited to the cohort in the cmRCT approach increases the statistical power of any randomised controlled trials and enables unequal randomisation. For example, a small number of patients could be randomly selected to be offered an expensive treatment and compared with a larger number of unselected patients. Unequal randomisation thus improves the efficiency of trials of high cost interventions compared with equal allocation. These factors strengthen the inferences in the trial, lower treatment costs compared with standard designs (that is, once the cohort is established, it potentially allows for rapid and cheap recruitment of patients for any randomised controlled trials), and allows significant cost savings for trials of expensive treatments. Furthermore, data on treatment refusers provides information on the acceptability of the treatment and thus the generalisability of the trial results. \u003C\/p\u003E\u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-12\u0022\u003E\u003Ch2\u003ERole of the cmRCT design\u003C\/h2\u003E\u003Cp id=\u0022p-39\u0022\u003EThere are certain circumstances, populations, clinical conditions, and treatments where the cmRCT design is more, or less, suitable than current strategies (box). The approach is best suited to the examination of long term conditions for which many pragmatic clinical trials will likely be conducted in the future. The design is also suitable for both primary and secondary care settings, and for conditions with easily reported patient outcomes.\u003C\/p\u003E\u003Cdiv class=\u0022style2\u0022 id=\u0022boxed-text-1\u0022\u003E\u003Cdiv id=\u0022sec-13\u0022 class=\u0022subsection\u0022\u003E\u003Ch4\u003EUsing the cohort multiple randomised controlled trial design\u003C\/h4\u003E\u003Cdiv id=\u0022sec-14\u0022 class=\u0022subsection\u0022\u003E\u003Ch5\u003EMost suited to: \u003C\/h5\u003E\u003Cdiv id=\u0022sec-15\u0022 class=\u0022subsection\u0022\u003E\u003Ch6\u003ESettings\u003C\/h6\u003E\u003Cul class=\u0022list-unord\u0022 id=\u0022list-4\u0022\u003E\u003Cli id=\u0022list-item-13\u0022\u003E\u003Cp id=\u0022p-40\u0022\u003EOpen trials with \u201ctreatment as usual\u201d as the comparator\u003C\/p\u003E\u003C\/li\u003E\u003Cli id=\u0022list-item-14\u0022\u003E\u003Cp id=\u0022p-41\u0022\u003EStudies that aim to inform healthcare decisions in routine practice (pragmatic trials)\u003C\/p\u003E\u003C\/li\u003E\u003Cli id=\u0022list-item-15\u0022\u003E\u003Cp id=\u0022p-42\u0022\u003EResearch questions that address easily measured and collected outcomes \u003C\/p\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv id=\u0022sec-16\u0022 class=\u0022subsection\u0022\u003E\u003Ch6\u003EPopulations\u003C\/h6\u003E\u003Cul class=\u0022list-unord\u0022 id=\u0022list-5\u0022\u003E\u003Cli id=\u0022list-item-16\u0022\u003E\u003Cp id=\u0022p-43\u0022\u003EStable populations\u003C\/p\u003E\u003C\/li\u003E\u003Cli id=\u0022list-item-17\u0022\u003E\u003Cp id=\u0022p-44\u0022\u003EEasily identified populations\u003C\/p\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv id=\u0022sec-17\u0022 class=\u0022subsection\u0022\u003E\u003Ch6\u003EClinical conditions\u003C\/h6\u003E\u003Cul class=\u0022list-unord\u0022 id=\u0022list-6\u0022\u003E\u003Cli id=\u0022list-item-18\u0022\u003E\u003Cp id=\u0022p-45\u0022\u003EClinical conditions for which many trials will be conducted; for example, obesity, diabetes, chronic pain \u003C\/p\u003E\u003C\/li\u003E\u003Cli id=\u0022list-item-19\u0022\u003E\u003Cp id=\u0022p-46\u0022\u003EChronic conditions\u003C\/p\u003E\u003C\/li\u003E\u003Cli id=\u0022list-item-20\u0022\u003E\u003Cp id=\u0022p-47\u0022\u003EConditions for which previous trials have struggled with recruitment\u003C\/p\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv id=\u0022sec-18\u0022 class=\u0022subsection\u0022\u003E\u003Ch6\u003ETreatments\u003C\/h6\u003E\u003Cul class=\u0022list-unord\u0022 id=\u0022list-7\u0022\u003E\u003Cli id=\u0022list-item-21\u0022\u003E\u003Cp id=\u0022p-48\u0022\u003ETreatments highly desired by patients\u003C\/p\u003E\u003C\/li\u003E\u003Cli id=\u0022list-item-22\u0022\u003E\u003Cp id=\u0022p-49\u0022\u003EExpensive treatments\u003C\/p\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cdiv id=\u0022sec-19\u0022 class=\u0022subsection\u0022\u003E\u003Ch5\u003ELeast suited to:\u003C\/h5\u003E\u003Cdiv id=\u0022sec-20\u0022 class=\u0022subsection\u0022\u003E\u003Ch6\u003ESettings\u003C\/h6\u003E\u003Cul class=\u0022list-unord\u0022 id=\u0022list-8\u0022\u003E\u003Cli id=\u0022list-item-23\u0022\u003E\u003Cp id=\u0022p-50\u0022\u003EClosed trial designs with masking or a placebo arm\u003C\/p\u003E\u003C\/li\u003E\u003Cli id=\u0022list-item-24\u0022\u003E\u003Cp id=\u0022p-51\u0022\u003EStudies that aim to further knowledge as to how and why a treatment works (efficacy trials) \u003C\/p\u003E\u003C\/li\u003E\u003Cli id=\u0022list-item-25\u0022\u003E\u003Cp id=\u0022p-52\u0022\u003EResearch questions that address hard to measure and hard to collect outcomes\u003C\/p\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv id=\u0022sec-21\u0022 class=\u0022subsection\u0022\u003E\u003Ch6\u003EPopulation\u003C\/h6\u003E\u003Cul class=\u0022list-unord\u0022 id=\u0022list-9\u0022\u003E\u003Cli id=\u0022list-item-26\u0022\u003E\u003Cp id=\u0022p-53\u0022\u003EPopulations with high attrition\u003C\/p\u003E\u003C\/li\u003E\u003Cli id=\u0022list-item-27\u0022\u003E\u003Cp id=\u0022p-54\u0022\u003EUnstable patient populations\u003C\/p\u003E\u003C\/li\u003E\u003Cli id=\u0022list-item-28\u0022\u003E\u003Cp id=\u0022p-55\u0022\u003EDifficult to identify populations\u003C\/p\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv id=\u0022sec-22\u0022 class=\u0022subsection\u0022\u003E\u003Ch6\u003EClinical conditions\u003C\/h6\u003E\u003Cul class=\u0022list-unord\u0022 id=\u0022list-10\u0022\u003E\u003Cli id=\u0022list-item-29\u0022\u003E\u003Cp id=\u0022p-56\u0022\u003EAcute or short term conditions \u003C\/p\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv id=\u0022sec-23\u0022 class=\u0022subsection\u0022\u003E\u003Ch6\u003ETreatments\u003C\/h6\u003E\u003Cul class=\u0022list-unord\u0022 id=\u0022list-11\u0022\u003E\u003Cli id=\u0022list-item-30\u0022\u003E\u003Cp id=\u0022p-57\u0022\u003ETreatments not highly desired by patients\u003C\/p\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-58\u0022\u003EThe cmRCT design cannot be used for trials that have a placebo comparator because such trials could not use feature VI (comparison to treatment as usual) or feature VII (patient centred informed consent) as patients are never told that they may receive placebo in routine health care. However, features I to V could be used for placebo trials and benefits A to E would still accrue.\u003C\/p\u003E\u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-24\u0022\u003E\u003Ch2\u003EChallenges of the design\u003C\/h2\u003E\u003Cp id=\u0022p-59\u0022\u003EA potential problem with our approach is that significant numbers of patients may refuse to receive the intervention being trialled. An intention to treat analysis will, therefore, dilute any treatment effects. There are two ways of dealing with this problem. Firstly, we could use the statistical method complier average causal effect (CACE) analysis,\u003Ca id=\u0022xref-ref-20-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-20\u0022\u003E20\u003C\/a\u003E which provides unbiased estimates of the treatment effect for patients who comply with the protocol (albeit usually with loss of power), unlike per protocol or on treatment analysis. \u003C\/p\u003E\u003Cp id=\u0022p-60\u0022\u003ESecondly, we could try to avoid some potential non-compliance by presenting cohort patients with a list of possible interventions at enrolment and asking which they would consider agreeing to use if offered. This process identifies the potential compliers in advance and consequently reduces dilution effects; however, care must be taken to avoid false expectation of future treatment and the loss of feature VII, patient centred information and consent. \u003C\/p\u003E\u003Cp id=\u0022p-61\u0022\u003EIn researching interventions already available in routine health care, it will be necessary to identify and monitor which patients use or have used these. \u003C\/p\u003E\u003Cp id=\u0022p-62\u0022\u003EFurthermore, discrete trials are currently supported by private and public funding infrastructures and institutional frameworks, to the tune of \u00a3100\u2009000 per trial. Existing infrastructures and frameworks might struggle to determine a funding approach for cmRCTs.\u003C\/p\u003E\u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-25\u0022\u003E\u003Ch2\u003EExamples of the cmRCT design\u003C\/h2\u003E\u003Cp id=\u0022p-63\u0022\u003ECampbell and colleagues\u003Ca id=\u0022xref-ref-18-2\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-18\u0022\u003E18\u003C\/a\u003E recently adapted the randomised consent (Zelen) method and developed an approach in which patients consented to an observational study and were then all randomly allocated to either intervention or control in a randomised controlled trial. Although this method shares several features with the cmRCT design (features I, II, IV, and VII), it does not have the capacity for multiple randomised controlled trials (feature III) or use random selection of some instead of random allocation of all (features V and VI).\u003C\/p\u003E\u003Cp id=\u0022p-64\u0022\u003EWe have obtained ethical approval for and have conducted a pilot study of the cmRCT design.\u003Ca id=\u0022xref-ref-21-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-21\u0022\u003E21\u003C\/a\u003E In this pilot, a large observational cohort of 856 women aged 45-64 was recruited and their outcomes measured. A total of 72 women reported frequent or severe menopausal hot flushes, or both. Of these 72 women, 48 were eligible for the trial treatment (NA) and 24 were randomly selected to be offered the treatment (nA). The outcomes of the randomly selected patients were then compared with the outcomes of those eligible patients not randomly selected (NA \u2212 nA) using both intention to treat analysis and CACE analysis.\u003Ca id=\u0022xref-ref-20-2\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-20\u0022\u003E20\u003C\/a\u003E Patients were not told about the treatments that they were not randomly selected to be offered. \u003C\/p\u003E\u003Cp id=\u0022p-65\u0022\u003EThe clinical outcomes of this pilot will be reported separately. However, a post hoc evaluation of the design found that the design was acceptable to patients, clinicians, and the NHS Research ethics committee. The concept of multiple trials within a single cohort of patients (feature III) has not yet been tested.\u003C\/p\u003E\u003Cp id=\u0022p-66\u0022\u003EThe cmRCT design is currently being used to address questions in the management of obesity (\u003Ca href=\u0022http:\/\/clahrc-sy.nihr.ac.uk\/theme-obesity.html\u0022\u003Ehttp:\/\/clahrc-sy.nihr.ac.uk\/theme-obesity.html\u003C\/a\u003E). The 20 year study is projected to recruit a cohort of 20\u2009000 adults aged 16 years or more, and multiple trials will be embedded within this cohort. To maximise the long term benefits of this study, it is planned that the cohort will be \u201copen\u201d and will be replenished with new recruits (16 and 17 year olds) every two years.\u003C\/p\u003E\u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-26\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\u003Cp id=\u0022p-67\u0022\u003EThe cmRCT design appears to be a workable and useful approach to pragmatic research questions that aim to inform healthcare decisions within routine practice. The design is best suited to circumstances that require open (rather than blinded) trials where \u201ctreatment as usual\u201d is compared with the offer of study treatment, and to questions with outcomes that can be easily measured in the whole cohort (for example, patient reported outcomes). Clinical conditions where many clinical trials will be conducted and trials of desirable or expensive interventions are also well suited to the cmRCT approach.\u003C\/p\u003E\u003Cp id=\u0022p-68\u0022\u003EThere are challenges to the cmRCT design. Further research is required to address a range of analysis and implementation questions related to the design and the ethics of patient centred informed consent for pragmatic randomised controlled trials. \u003C\/p\u003E\u003Cp id=\u0022p-69\u0022\u003EIn his Harveian oration at the Royal College of Physicians, London, Professor Michael Rawlins, chair of the National Institute for Health and Clinical Excellence, called for \u201cinvestigators to continue to develop and improve their methodologies in order to help decision makers appraise the evidence.\u201d\u003Ca id=\u0022xref-ref-22-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-22\u0022\u003E22\u003C\/a\u003E We hope that the cmRCT design goes some way towards addressing the problems associated with existing approaches. If these problems are addressed, then perhaps the most important problem of all will be resolved\u2014the non-implementation of the results of clinical research.\u003C\/p\u003E\u003Cdiv class=\u0022style1\u0022 id=\u0022boxed-text-2\u0022\u003E\u003Cdiv id=\u0022sec-27\u0022 class=\u0022subsection\u0022\u003E\u003Ch4\u003ESummary points\u003C\/h4\u003E\u003Cul class=\u0022list-simple\u0022 id=\u0022list-12\u0022\u003E\u003Cli id=\u0022list-item-31\u0022\u003E\u003Cp id=\u0022p-70\u0022\u003EThe \u201ccohort multiple randomised controlled trial\u201d (cmRCT) design tackles some of the problems associated with pragmatic trial designs, such as recruitment\u003C\/p\u003E\u003C\/li\u003E\u003Cli id=\u0022list-item-32\u0022\u003E\u003Cp id=\u0022p-71\u0022\u003EThe cmRCT design has several innovative features: a large observational cohort of patients is recruited and used as a multiple trials facility; each randomised controlled trial uses random selection of some participants (not random allocation of all); and \u201cpatient centred\u201d information and consent is applied\u003C\/p\u003E\u003C\/li\u003E\u003Cli id=\u0022list-item-33\u0022\u003E\u003Cp id=\u0022p-72\u0022\u003EThe cmRCT design is best suited to: open trials where \u201ctreatment as usual\u201d is compared with the offer of treatment; easily measured and collected outcomes; conditions where many trials will be conducted; and trials of desirable or expensive interventions\u003C\/p\u003E\u003C\/li\u003E\u003Cli id=\u0022list-item-34\u0022\u003E\u003Cp id=\u0022p-73\u0022\u003EFurther research is required to address a range of analysis, implementation, and ethical questions related to the cmRCT design\u003C\/p\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cdiv class=\u0022section notes\u0022 id=\u0022notes-2\u0022\u003E\u003Ch2\u003ENotes\u003C\/h2\u003E\u003Cp id=\u0022p-79\u0022\u003E\u003Cstrong\u003ECite this as:\u003C\/strong\u003E \u003Cem\u003EBMJ\u003C\/em\u003E 2010;340:c1066\u003C\/p\u003E\u003C\/div\u003E\u003Cdiv class=\u0022section fn-group\u0022 id=\u0022fn-group-1\u0022\u003E\u003Ch2\u003EFootnotes\u003C\/h2\u003E\u003Cul\u003E\u003Cli class=\u0022fn-participating-researchers\u0022 id=\u0022fn-1\u0022\u003E\u003Cp id=\u0022p-74\u0022\u003EContributors: JN and CR had the original idea for the article. This article arose from CR\u2019s doctoral research, which was supervised by JN and AO at the School for Health and Related Research at the University of Sheffield. CR wrote the article and prepared the initial and subsequent draft. JN reviewed and commented on every draft. AO and DT commented on later drafts. AO, DT, CR, and JN agreed the final draft. CR is guarantor for the article. JN and CR jointly conceived the cmRCT design.\u003C\/p\u003E\u003C\/li\u003E\u003Cli class=\u0022fn-financial-disclosure\u0022 id=\u0022fn-2\u0022\u003E\u003Cp id=\u0022p-75\u0022\u003EFunding: A pre-doctoral training fellowship award from the Department of Health\u2019s National Coordinating Centre for Research Capacity Development funded CR\u2019s doctoral research and the pilot of the cmRCT design. All work has been independent from the funders in every way. \u003C\/p\u003E\u003C\/li\u003E\u003Cli class=\u0022fn-conflict\u0022 id=\u0022fn-3\u0022\u003E\u003Cp id=\u0022p-76\u0022\u003ECompeting interests: All authors have completed the Unified Competing Interest form at \u003Ca href=\u0022http:\/\/www.icmje.org\/coi_disclosure.pdf\u0022\u003Ewww.icmje.org\/coi_disclosure.pdf\u003C\/a\u003E (available on request from the corresponding author) and declare that (1) CR, AOC, and JN have received financial support from the University of Sheffield and DT has received financial support from the University of York for the submitted work; (2) CR, AOC, JN, and DT have no relationships with any companies that might have an interest in the submitted work in the previous three years; (3) their spouses, partners, or children have no financial relationships that may be relevant to the submitted work; and (4) no author has any non-financial interests that may be relevant to the submitted work.\u003C\/p\u003E\u003C\/li\u003E\u003Cli class=\u0022fn\u0022 id=\u0022fn-4\u0022\u003E\u003Cp id=\u0022p-77\u0022\u003EEthical approval: The protocol of the cmRCT pilot study was approved by the South Sheffield NHS Research Ethics Committee (ref 06\/Q2305\/181). NHS Scientific Review Approval was also obtained (consortium ref: ZF89).\u003C\/p\u003E\u003C\/li\u003E\u003Cli class=\u0022fn\u0022 id=\u0022fn-5\u0022\u003E\u003Cp id=\u0022p-78\u0022\u003EProvenance and peer review: Not commissioned; externally peer reviewed.\u003C\/p\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022section ref-list\u0022 id=\u0022ref-list-1\u0022\u003E\u003Ch2\u003EReferences\u003C\/h2\u003E\u003Col class=\u0022cit-list\u0022\u003E\u003Cli\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-1-1\u0022 title=\u0022View reference 1 in text\u0022 id=\u0022ref-1\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-journal\u0022 id=\u0022cit-340.mar19_1.c1066.1\u0022 data-doi=\u002210.1016\/0021-9681(67)90041-0\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003ESchwartz D, Lellouch J. Explanatory and pragmatic attitudes in therapeutical trials. \u003Cabbr class=\u0022cit-jnl-abbrev\u0022\u003EJ Chronic Dis\u003C\/abbr\u003E\u003Cspan class=\u0022cit-pub-date\u0022\u003E1967\u003C\/span\u003E;\u003Cspan class=\u0022cit-vol\u0022\u003E20\u003C\/span\u003E:\u003Cspan class=\u0022cit-fpage\u0022\u003E637\u003C\/span\u003E-48. \u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003Ca href=\u0022{openurl}?query=rft.jtitle%253DJournal%2Bof%2Bchronic%2Bdiseases%26rft.stitle%253DJ%2BChronic%2BDis%26rft.aulast%253DSchwartz%26rft.auinit1%253DD.%26rft.volume%253D20%26rft.issue%253D8%26rft.spage%253D637%26rft.epage%253D648%26rft.atitle%253DExplanatory%2Band%2Bpragmatic%2Battitudes%2Bin%2Btherapeutical%2Btrials.%26rft_id%253Dinfo%253Adoi%252F10.1016%252F0021-9681%252867%252990041-0%26rft_id%253Dinfo%253Apmid%252F4860352%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url\u0022\u003E\u003Cspan\u003EOpenUrl\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=10.1016\/0021-9681(67)90041-0\u0026amp;link_type=DOI\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref\u0022\u003E\u003Cspan\u003ECrossRef\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=4860352\u0026amp;link_type=MED\u0026amp;atom=%2Fbmj%2F340%2Fbmj.c1066.atom\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-medline\u0022\u003E\u003Cspan\u003EPubMed\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=A19679847800009\u0026amp;link_type=ISI\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-newisilink cit-ref-sprinkles-webofscience\u0022\u003E\u003Cspan\u003EWeb of Science\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-2-1\u0022 title=\u0022View reference 2 in text\u0022 id=\u0022ref-2\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-journal\u0022 id=\u0022cit-340.mar19_1.c1066.2\u0022 data-doi=\u002210.1016\/j.jclinepi.2008.12.011\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003EThorpe KE, Zwarenstein M, Oxman AD, Treweek S, Furberg CD, Altman DG, et al. A pragmatic-explanatory continuum indicator summary (PRECIS): a tool to help trial designers. \u003Cabbr class=\u0022cit-jnl-abbrev\u0022\u003EJ Clin Epidemiol\u003C\/abbr\u003E\u003Cspan class=\u0022cit-pub-date\u0022\u003E2009\u003C\/span\u003E;\u003Cspan class=\u0022cit-vol\u0022\u003E62\u003C\/span\u003E:\u003Cspan class=\u0022cit-fpage\u0022\u003E464\u003C\/span\u003E-75.\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003Ca href=\u0022{openurl}?query=rft.jtitle%253DJournal%2Bof%2Bclinical%2Bepidemiology%26rft.stitle%253DJ%2BClin%2BEpidemiol%26rft.aulast%253DThorpe%26rft.auinit1%253DK.%2BE.%26rft.volume%253D62%26rft.issue%253D5%26rft.spage%253D464%26rft.epage%253D475%26rft.atitle%253DA%2Bpragmatic-explanatory%2Bcontinuum%2Bindicator%2Bsummary%2B%2528PRECIS%2529%253A%2Ba%2Btool%2Bto%2Bhelp%2Btrial%2Bdesigners.%26rft_id%253Dinfo%253Adoi%252F10.1016%252Fj.jclinepi.2008.12.011%26rft_id%253Dinfo%253Apmid%252F19348971%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url\u0022\u003E\u003Cspan\u003EOpenUrl\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=10.1016\/j.jclinepi.2008.12.011\u0026amp;link_type=DOI\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref\u0022\u003E\u003Cspan\u003ECrossRef\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=19348971\u0026amp;link_type=MED\u0026amp;atom=%2Fbmj%2F340%2Fbmj.c1066.atom\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-medline\u0022\u003E\u003Cspan\u003EPubMed\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=000265424400002\u0026amp;link_type=ISI\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-newisilink cit-ref-sprinkles-webofscience\u0022\u003E\u003Cspan\u003EWeb of Science\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-3-1\u0022 title=\u0022View reference 3 in text\u0022 id=\u0022ref-3\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-journal\u0022 id=\u0022cit-340.mar19_1.c1066.3\u0022 data-doi=\u002210.1186\/1745-6215-7-9\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003EMcDonald AM, Knight RC, Campbell MK, Entwistle VA, Grant AM, Cook JA, et al. What influences recruitment to randomised controlled trials? 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Should you tell patients about beneficial treatments that they cannot have? \u003Cabbr class=\u0022cit-jnl-abbrev\u0022\u003EBMJ\u003C\/abbr\u003E\u003Cspan class=\u0022cit-pub-date\u0022\u003E2007\u003C\/span\u003E;\u003Cspan class=\u0022cit-vol\u0022\u003E334\u003C\/span\u003E:\u003Cspan class=\u0022cit-fpage\u0022\u003E826\u003C\/span\u003E.\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003Ca href=\u0022{openurl}?query=rft.jtitle%253DBMJ%26rft.stitle%253DBMJ%26rft.issn%253D0007-1447%26rft.aulast%253DMarcus%26rft.auinit1%253DR.%26rft.volume%253D334%26rft.issue%253D7598%26rft.spage%253D826%26rft.epage%253D826%26rft.atitle%253DShould%2Byou%2Btell%2Bpatients%2Babout%2Bbeneficial%2Btreatments%2Bthat%2Bthey%2Bcannot%2Bhave%253F%2BYes%26rft_id%253Dinfo%253Adoi%252F10.1136%252Fbmj.39171.426690.AD%26rft_id%253Dinfo%253Apmid%252F17446611%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url\u0022\u003E\u003Cspan\u003EOpenUrl\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/ijlink\/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiRlVMTCI7czoxMToiam91cm5hbENvZGUiO3M6MzoiYm1qIjtzOjU6InJlc2lkIjtzOjEyOiIzMzQvNzU5OC84MjYiO3M6NDoiYXRvbSI7czoyMzoiL2Jtai8zNDAvYm1qLmMxMDY2LmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-ijlink\u0022\u003E\u003Cspan\u003E\u003Cspan class=\u0022cit-reflinks-full-text\u0022\u003E\u003Cspan class=\u0022free-full-text\u0022\u003EFREE \u003C\/span\u003EFull Text\u003C\/span\u003E\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-9-1\u0022 title=\u0022View reference 9 in text\u0022 id=\u0022ref-9\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-other\u0022 id=\u0022cit-340.mar19_1.c1066.9\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003ETorgerson DJ, Torgerson CJ. \u003Cspan class=\u0022cit-source\u0022\u003EDesigning randomised trials in health, education and the social sciences: an introduction\u003C\/span\u003E. Palgrave Macmillan, \u003Cspan class=\u0022cit-pub-date\u0022\u003E2008\u003C\/span\u003E.\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-10-1\u0022 title=\u0022View reference 10 in text\u0022 id=\u0022ref-10\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-journal\u0022 id=\u0022cit-340.mar19_1.c1066.10\u0022 data-doi=\u002210.1136\/bmj.326.7387.472\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003ESong F, Altman DG, Glenny AM, Deeks JJ. Validity of indirect comparison for estimating efficacy of competing interventions: empirical evidence from published meta-analyses. \u003Cabbr class=\u0022cit-jnl-abbrev\u0022\u003EBMJ\u003C\/abbr\u003E\u003Cspan class=\u0022cit-pub-date\u0022\u003E2003\u003C\/span\u003E;\u003Cspan class=\u0022cit-vol\u0022\u003E326\u003C\/span\u003E:\u003Cspan class=\u0022cit-fpage\u0022\u003E472\u003C\/span\u003E-7.\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003Ca href=\u0022{openurl}?query=rft.jtitle%253DBMJ%26rft.stitle%253DBMJ%26rft.issn%253D0007-1447%26rft.aulast%253DSong%26rft.auinit1%253DF.%26rft.volume%253D326%26rft.issue%253D7387%26rft.spage%253D472%26rft.epage%253D472%26rft.atitle%253DValidity%2Bof%2Bindirect%2Bcomparison%2Bfor%2Bestimating%2Befficacy%2Bof%2Bcompeting%2Binterventions%253A%2Bempirical%2Bevidence%2Bfrom%2Bpublished%2Bmeta-analyses%26rft_id%253Dinfo%253Adoi%252F10.1136%252Fbmj.326.7387.472%26rft_id%253Dinfo%253Apmid%252F12609941%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url\u0022\u003E\u003Cspan\u003EOpenUrl\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/ijlink\/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MzoiYm1qIjtzOjU6InJlc2lkIjtzOjEyOiIzMjYvNzM4Ny80NzIiO3M6NDoiYXRvbSI7czoyMzoiL2Jtai8zNDAvYm1qLmMxMDY2LmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-ijlink\u0022\u003E\u003Cspan\u003E\u003Cspan class=\u0022cit-reflinks-abstract\u0022\u003EAbstract\u003C\/span\u003E\u003Cspan class=\u0022cit-sep cit-reflinks-variant-name-sep\u0022\u003E\/\u003C\/span\u003E\u003Cspan class=\u0022cit-reflinks-full-text\u0022\u003E\u003Cspan class=\u0022free-full-text\u0022\u003EFREE \u003C\/span\u003EFull Text\u003C\/span\u003E\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-11-1\u0022 title=\u0022View reference 11 in text\u0022 id=\u0022ref-11\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-journal\u0022 id=\u0022cit-340.mar19_1.c1066.11\u0022 data-doi=\u002210.1136\/bmj.299.6694.313\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003EBrewin CR, Bradley C. Patient preferences and randomised clinical trials. \u003Cabbr class=\u0022cit-jnl-abbrev\u0022\u003EBMJ\u003C\/abbr\u003E\u003Cspan class=\u0022cit-pub-date\u0022\u003E1989\u003C\/span\u003E;\u003Cspan class=\u0022cit-vol\u0022\u003E299\u003C\/span\u003E:\u003Cspan class=\u0022cit-fpage\u0022\u003E313\u003C\/span\u003E-5.\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003Ca href=\u0022{openurl}?query=rft.jtitle%253DBMJ%26rft.stitle%253DBMJ%26rft.issn%253D0007-1447%26rft.aulast%253DBrewin%26rft.auinit1%253DC.%2BR.%26rft.volume%253D299%26rft.issue%253D6694%26rft.spage%253D313%26rft.epage%253D315%26rft.atitle%253DPatient%2Bpreferences%2Band%2Brandomised%2Bclinical%2Btrials.%26rft_id%253Dinfo%253Adoi%252F10.1136%252Fbmj.299.6694.313%26rft_id%253Dinfo%253Apmid%252F2504416%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url\u0022\u003E\u003Cspan\u003EOpenUrl\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/ijlink\/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6MzoiUERGIjtzOjExOiJqb3VybmFsQ29kZSI7czozOiJibWoiO3M6NToicmVzaWQiO3M6MTI6IjI5OS82Njk0LzMxMyI7czo0OiJhdG9tIjtzOjIzOiIvYm1qLzM0MC9ibWouYzEwNjYuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-ijlink\u0022\u003E\u003Cspan\u003E\u003Cspan class=\u0022cit-reflinks-full-text\u0022\u003E\u003Cspan class=\u0022free-full-text\u0022\u003EFREE \u003C\/span\u003EFull Text\u003C\/span\u003E\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-12-1\u0022 title=\u0022View reference 12 in text\u0022 id=\u0022ref-12\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-journal\u0022 id=\u0022cit-340.mar19_1.c1066.12\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003EFrancis T Jr, Korns RF, Voight RB, Boisen M, Hemphill FM, Napier JA, et al. An evaluation of the 1954 poliomyelitis vaccine trials. \u003Cabbr class=\u0022cit-jnl-abbrev\u0022\u003EAm J Public Health\u003C\/abbr\u003E\u003Cspan class=\u0022cit-pub-date\u0022\u003E1954\u003C\/span\u003E;\u003Cspan class=\u0022cit-vol\u0022\u003E45\u003C\/span\u003E:\u003Cspan class=\u0022cit-fpage\u0022\u003E1\u003C\/span\u003E-63.\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003Ca href=\u0022{openurl}?query=rft.jtitle%253DAm%2BJ%2BPublic%2BHealth%26rft.volume%253D45%26rft.spage%253D1%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url\u0022\u003E\u003Cspan\u003EOpenUrl\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-13-1\u0022 title=\u0022View reference 13 in text\u0022 id=\u0022ref-13\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-journal\u0022 id=\u0022cit-340.mar19_1.c1066.13\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003EOlschewski M, Scheurlen H. Comprehensive cohort study: an alternative to randomised consent design in a breast preservation trial. \u003Cabbr class=\u0022cit-jnl-abbrev\u0022\u003EMethods Inf Med\u003C\/abbr\u003E\u003Cspan class=\u0022cit-pub-date\u0022\u003E1985\u003C\/span\u003E;\u003Cspan class=\u0022cit-vol\u0022\u003E24\u003C\/span\u003E:\u003Cspan class=\u0022cit-fpage\u0022\u003E131\u003C\/span\u003E-4.\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003Ca href=\u0022{openurl}?query=rft.jtitle%253DMethods%2Bof%2Binformation%2Bin%2Bmedicine%26rft.stitle%253DMethods%2BInf%2BMed%26rft.aulast%253DOlschewski%26rft.auinit1%253DM.%26rft.volume%253D24%26rft.issue%253D3%26rft.spage%253D131%26rft.epage%253D134%26rft.atitle%253DComprehensive%2BCohort%2BStudy%253A%2Ban%2Balternative%2Bto%2Brandomized%2Bconsent%2Bdesign%2Bin%2Ba%2Bbreast%2Bpreservation%2Btrial.%26rft_id%253Dinfo%253Apmid%252F4033443%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url\u0022\u003E\u003Cspan\u003EOpenUrl\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=4033443\u0026amp;link_type=MED\u0026amp;atom=%2Fbmj%2F340%2Fbmj.c1066.atom\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-medline\u0022\u003E\u003Cspan\u003EPubMed\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=A1985ANJ2600003\u0026amp;link_type=ISI\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-newisilink cit-ref-sprinkles-webofscience\u0022\u003E\u003Cspan\u003EWeb of Science\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-14-1\u0022 title=\u0022View reference 14 in text\u0022 id=\u0022ref-14\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-journal\u0022 id=\u0022cit-340.mar19_1.c1066.14\u0022 data-doi=\u002210.1056\/NEJM197905313002203\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003EZelen M. 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Patients\u2019 preferences within randomised trials: systematic review and patient level meta-analysis. \u003Cabbr class=\u0022cit-jnl-abbrev\u0022\u003EBMJ\u003C\/abbr\u003E\u003Cspan class=\u0022cit-pub-date\u0022\u003E2008\u003C\/span\u003E;\u003Cspan class=\u0022cit-vol\u0022\u003E337\u003C\/span\u003E:\u003Cspan class=\u0022cit-fpage\u0022\u003Ea1864\u003C\/span\u003E-6.\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003Ca href=\u0022{openurl}?query=rft.jtitle%253DBMJ%26rft.stitle%253DBMJ%26rft.issn%253D0007-1447%26rft.aulast%253DPreference%2BCollaborative%2BReview%2BGroup%26rft.auinit1%253D%2B%26rft.volume%253D337%26rft.issue%253Doct31_1%26rft.spage%253Da1864%26rft.epage%253Da1864%26rft.atitle%253DPatients%2527%2Bpreferences%2Bwithin%2Brandomised%2Btrials%253A%2Bsystematic%2Breview%2Band%2Bpatient%2Blevel%2Bmeta-analysis%26rft_id%253Dinfo%253Adoi%252F10.1136%252Fbmj.a1864%26rft_id%253Dinfo%253Apmid%252F18977792%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url\u0022\u003E\u003Cspan\u003EOpenUrl\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/ijlink\/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MzoiYm1qIjtzOjU6InJlc2lkIjtzOjE3OiIzMzcvb2N0MzFfMS9hMTg2NCI7czo0OiJhdG9tIjtzOjIzOiIvYm1qLzM0MC9ibWouYzEwNjYuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-ijlink\u0022\u003E\u003Cspan\u003E\u003Cspan class=\u0022cit-reflinks-abstract\u0022\u003EAbstract\u003C\/span\u003E\u003Cspan class=\u0022cit-sep cit-reflinks-variant-name-sep\u0022\u003E\/\u003C\/span\u003E\u003Cspan class=\u0022cit-reflinks-full-text\u0022\u003E\u003Cspan class=\u0022free-full-text\u0022\u003EFREE \u003C\/span\u003EFull Text\u003C\/span\u003E\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-16-1\u0022 title=\u0022View reference 16 in text\u0022 id=\u0022ref-16\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-journal\u0022 id=\u0022cit-340.mar19_1.c1066.16\u0022 data-doi=\u002210.1016\/j.cct.2005.11.003\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003EAdamson J, Cockayne S, Puffer S, Torgerson DJ. 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